tbuckley/cabot-search huggingface dataset:
Understanding breast cancer complexity to improve patient outcomes: The St Gallen International Consensus Conference for the Primary Therapy of Individuals with Early Breast Cancer 2023
Authors: G. Curigliano, H.J. Burstein, M. Gnant, S. Loibl, D. Cameron, M.M. Regan, C. Denkert, P. Poortmans, W.P. Weber, B. Thürlimann, S. Aebi, M. Al-Foheidi, F. André, M. Anikusko, R. Badwe, A.V. Barrio, C. Barrios, J. Bergh, H. Bonnefoi, D. Bretel Morales, S. Brucker, H.J. Burstein, C. Caldas, D. Cameron, F. Cardoso, M.J. Cardoso, L. Carey, S. Chia, C. Coles, J. Cortes, G. Curigliano, J. de Boniface, S. Delaloge, A. DeMichele, C. Denkert, G. Fastner, F. Fitzal, P. Francis, H. Gamal, O. Gentilini, M. Gnant, W. Gradishar, B. Gulluoglu, N. Harbeck, J. Heil, C.-S.H. Huang, J. Huober, Z. Jiang, O. Kaidar-Person, M. Kok, E.-S. Lee, S. Loi, S. Loibl, M. Martin, I. Meattini, M. Morrow, A. Partridge, F. Penault-Llorca, M. Piccart, L. Pierce, P. Poortmans, M. Regan, J. Reis-Filho, I. Rubio, H. Rugo, E. Rutgers, C. Saura, E. Senkus, Z. Shao, C. Singer, T. Spanic, B. Thuerlimann, M. Toi, S. Tolaney, N. Turner, A. Tutt, M.-J. Vrancken Peeters, T. Watanabe, W. Weber, H. Wildiers, B. Xu
Journal: Annals of Oncology (2023)

The 18th St Gallen International Breast Cancer Conference held in March 2023, in Vienna, Austria, assessed significant new findings for local and systemic therapies for early breast cancer with a focus on the evaluation of multimodal treatment options. The emergence of more effective, innovative agents in both the preoperative (primary or neoadjuvant) and post-operative (adjuvant) settings has underscored the pivotal role of a multidisciplinary approach in treatment decision making, particularly when selecting systemic therapy for an individual patient. The importance of multidisciplinary discussions regarding the clinical benefits of interventions was explicitly emphasized by the consensus panel as an integral part of developing an optimal treatment plan with the 'right' degree of intensity and duration. The panelists focused on controversies surrounding the management of common ductal/no special type and lobular breast cancer histology, which account for the vast majority of breast tumors. The expert opinion of the panelists was based on interpretations of available data, as well as current practices in their professional environments, personal and socioeconomic factors affecting patients, and cognizant of varying reimbursement and accessibility constraints around the world. The panelists strongly advocated patient participation in well-designed clinical studies whenever feasible. With these considerations in mind, the St Gallen Consensus Conference aims to offer guidance to clinicians regarding appropriate treatments for early-stage breast cancer and assist in balancing the realistic trade-offs between treatment benefit and toxicity, enabling patients and clinicians to make well-informed choices through a shared decision-making process.
A review of supine position related obstructive sleep apnea: Classification, epidemiology, pathogenesis and treatment
Authors: Shane A. Landry, Caroline Beatty, Luke D.J. Thomson, Ai-Ming Wong, Bradley A. Edwards, Garun S. Hamilton, Simon A. Joosten
Journal: Sleep Medicine Reviews (2023)

Supine related obstructive sleep apnea (OSA) is the most common clinical and physiological phenotype of OSA. This condition is recognizable by patients, their families and through polysomnographic recordings. Commonly used definitions distinguish the presence of supine related OSA when respiratory events occur at twice the frequency when the patient lies in the supine compared to non-supine sleeping positions. Recent physiology studies have demonstrated that airway obstruction arises more commonly in the supine position particularly at the level of the soft palate and epiglottis. Increased airway collapsibility is reliability observed supine relative to lateral position. To a lesser extent, changes in control of breathing favour less stable ventilation when the supine sleeping posture is adopted. Many treatments have been developed and trialled to help patients avoid sleeping on their back. The last 10 years has seen the emergence of vibrotactile warning devices that are worn on the patients' neck or chest. High quality randomized controlled trial data is accumulating on the efficacy and common pitfalls of the application of these treatments.
A clinically applicable AI system for diagnosis of congenital heart diseases based on computed tomography images
Authors: Xiaowei Xu, Qianjun Jia, Haiyun Yuan, Hailong Qiu, Yuhao Dong, Wen Xie, Zeyang Yao, Jiawei Zhang, Zhiqaing Nie, Xiaomeng Li, Yiyu Shi, James Y. Zou, Meiping Huang, Jian Zhuang
Journal: Medical Image Analysis (2023)
The functional impact of rare variation across the regulatory cascade
Authors: Taibo Li, Nicole Ferraro, Benjamin J. Strober, Francois Aguet, Silva Kasela, Marios Arvanitis, Bohan Ni, Laurens Wiel, Elliot Hershberg, Kristin Ardlie, Dan E. Arking, Rebecca L. Beer, Jennifer Brody, Thomas W. Blackwell, Clary Clish, Stacey Gabriel, Robert Gerszten, Xiuqing Guo, Namrata Gupta, W. Craig Johnson, Tuuli Lappalainen, Henry J. Lin, Yongmei Liu, Deborah A. Nickerson, George Papanicolaou, Jonathan K. Pritchard, Pankaj Qasba, Ali Shojaie, Josh Smith, Nona Sotoodehnia, Kent D. Taylor, Russell P. Tracy, David Van Den Berg, Matthew T. Wheeler, Stephen S. Rich, Jerome I. Rotter, Alexis Battle, Stephen B. Montgomery
Journal: Cell Genomics (2023)

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.
Effects of design consistency measures and roadside hazard types on run-off-road crash severity: Application of random parameters hierarchical ordered probit model
Authors: Shinthia Azmeri Khan, Shamsunnahar Yasmin, Md Mazharul Haque
Journal: Analytic Methods in Accident Research (2023)

Run-off-road crashes are one of the most significant causes of road deaths worldwide. Given such significant safety concerns, a number of earlier studies examined the critical factors contributing towards run-off-road crash severity outcomes, mostly by using the information compiled in the official crash database. However, the official crash databases are less likely to have detailed information on driver behavior (errors/expectations) and roadway environment (roadway geometry and roadside attributes). This study aims to investigate the effects of design consistency measures on run-off-road crash severity mechanisms by applying a random parameters hierarchical ordered Probit model. This study contributes towards existing safety literature by demonstrating a complementary approach to capturing the effects of driver behavior and heterogeneity in roadway environment on run-off-road crash severity outcome through the composite measures of design consistency indices and cosmopolite measures of roadside hazard type variables. Specifically, 17 different functional forms of design consistency indices are developed to capture the behavioral factors from the road-geometric changes in developing run-off-road crash severity models. Further, in examining the effect of different types of the roadside environment on run-off-road crash severity outcomes, seven roadside hazard type variables are generated as a composite function of roadside object type and clear zone (lateral distance to roadside object). The empirical analysis of this study involves a two-step modelling approach - in the first step, the decision tree algorithm is applied to identify the higher-order interaction among independent variables, and in the second step, crash severity models are developed by employing several econometric approaches. The hybrid models are estimated by employing four econometric frameworks, which include Ordered Probit, Hierarchical Ordered Probit, Random Parameters Ordered Probit, and Random parameters Hierarchical Ordered Probit models. The run-off-road crash severity models are estimated by using crash data collected from the State of Queensland, Australia, for the years 2015 through 2019. Overall, this study reveals the importance of considering the interaction of drivers' behavior, road geometry, and roadside attributes along with other independent variables in developing run-off-road crash severity models.
Restoration of Foxp3<sup>+</sup> Regulatory T Cells by HDAC-Dependent Epigenetic Modulation Plays a Pivotal Role in Resolving Pulmonary Arterial Hypertension Pathology
Authors: Chien-Nien Chen, Nabil Hajji, Fu-Chiang Yeh, Sunniyat Rahman, Souad Ali, John Wharton, Nicoleta Baxan, Lin Zhao, Chong-Yang Xie, Yi-Guan Chen, Maria G. Frid, Prakash Chelladurai, Soni Savai Pullamsetti, Kurt R. Stenmark, Martin R. Wilkins, Lan Zhao
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects in vivo, ex vivo, and in vitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.
HLA-B27, axial spondyloarthritis and survival
Authors: Zhixiu Li, Mohammad Kazim Khan, Sjef M van der Linden, Bjorn Winkens, Peter M Villiger, Heinz Baumberger, Hermine van Zandwijk, Muhammad Asim Khan, Matthew A Brown
Journal: Annals of the Rheumatic Diseases (2023)

Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data.In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths).AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed.AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.
Directed differentiation of human pluripotent stem cells into articular cartilage reveals effects caused by absence of<i>WISP3</i>, the gene responsible for progressive pseudorheumatoid arthropathy of childhood
Authors: Chaochang Li, Mireia Alemany-Ribes, Rosanne M Raftery, Uzochi Nwoko, Matthew L Warman, April M Craft
Journal: Annals of the Rheumatic Diseases (2023)

Progressive pseudorheumatoid arthropathy of childhood (PPAC), caused by deficiency of
Structure and function of rice hybrid genomes reveal genetic basis and optimal performance of heterosis
Authors: Zhoulin Gu, Junyi Gong, Zhou Zhu, Zhen Li, Qi Feng, Changsheng Wang, Yan Zhao, Qilin Zhan, Congcong Zhou, Ahong Wang, Tao Huang, Lei Zhang, Qilin Tian, Danlin Fan, Yiqi Lu, Qiang Zhao, Xuehui Huang, Shihua Yang, Bin Han
Journal: Nature Genetics (2023)

Abstract Exploitation of crop heterosis is crucial for increasing global agriculture production. However, the quantitative genomic analysis of heterosis was lacking, and there is currently no effective prediction tool to optimize cross-combinations. Here 2,839 rice hybrid cultivars and 9,839 segregation individuals were resequenced and phenotyped. Our findings demonstrated that indica – indica hybrid-improving breeding was a process that broadened genetic resources, pyramided breeding-favorable alleles through combinatorial selection and collaboratively improved both parents by eliminating the inferior alleles at negative dominant loci. Furthermore, we revealed that widespread genetic complementarity contributed to indica – japonica intersubspecific heterosis in yield traits, with dominance effect loci making a greater contribution to phenotypic variance than overdominance effect loci. On the basis of the comprehensive dataset, a genomic model applicable to diverse rice varieties was developed and optimized to predict the performance of hybrid combinations. Our data offer a valuable resource for advancing the understanding and facilitating the utilization of heterosis in rice.
Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA
Authors: Bowen Li, Allen Yujie Jiang, Idris Raji, Caroline Atyeo, Theresa M. Raimondo, Akiva G. R. Gordon, Luke H. Rhym, Tahoura Samad, Corina MacIsaac, Jacob Witten, Haseeb Mughal, Taras M. Chicz, Yue Xu, Ryan P. McNamara, Sangeeta Bhatia, Galit Alter, Robert Langer, Daniel G. Anderson
Journal: Nature Biomedical Engineering (2023)
Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer
Authors: Sandra Santasusagna, Shijia Zhu, Vijayakumar Jawalagatti, Marc Carceles-Cordon, Adam Ertel, Saioa Garcia-Longarte, Won-Min Song, Naoto Fujiwara, Peiyao Li, Isabel Mendizabal, Daniel P. Petrylak, William Kevin Kelly, E. Premkumar Reddy, Liguo Wang, Matthew J. Schiewer, Amaia Lujambio, Jeffrey Karnes, Karen E. Knudsen, Carlos Cordon-Cardo, Haidong Dong, Haojie Huang, Arkaitz Carracedo, Yujin Hoshida, Veronica Rodriguez-Bravo, Josep Domingo-Domenech
Journal: Cancer Discovery (2023)

Abstract Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)–dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5′ untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti–PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies. Significance: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489
Addendum 1:<i>Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma</i>
Journal: Journal for ImmunoTherapy of Cancer (2023)

the United States (US) Food and Drug Administration (FDA) approved tremelimumab in combination with durvalumab for adult patients with unresectable HCC.Approval was based on statistically significant and clinically meaningful improvement in overall survival for tremelimumab plus durvalumab compared to sorafenib in the phase III HIMALAYA trial (NCT03298451), which enrolled patients with confirmed unresectable HCC who had not received prior systemic treatment.In light of the approval, the 'Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma' has been updated.The following changes have been made to the manuscript.
Fulvestrant increases the susceptibility of enzalutamide-resistant prostate cancer cells to NK-mediated lysis
Authors: Madeline Dahut, Kristen Fousek, Lucas A Horn, Shantel Angstadt, Haiyan Qin, Duane H Hamilton, Jeffrey Schlom, Claudia Palena
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been shown to improve time to progression and extend overall survival in men with CRPC, the majority of patients ultimately develop resistance to treatment. Immunotherapy approaches have shown limited clinical benefit in this patient population; understanding resistance mechanisms could help develop novel and more effective treatments for CRPC. One of the mechanisms involved in tumor resistance to various therapeutics is tumor phenotypic plasticity, whereby carcinoma cells acquire mesenchymal features with or without the loss of classical epithelial characteristics. This work investigated a potential link between enzalutamide resistance, tumor phenotypic plasticity, and resistance to immune-mediated lysis in prostate cancer. Methods Models of prostate cancer resistant to enzalutamide were established by long-term exposure of human prostate cancer cell lines to the drug in culture. Tumor cells were evaluated for phenotypic features in vitro and in vivo, as well as for sensitivity to immune effector cell-mediated cytotoxicity. Results Resistance to enzalutamide was associated with gain of mesenchymal tumor features, upregulation of estrogen receptor expression, and significantly reduced tumor susceptibility to natural killer (NK)-mediated lysis, an effect that was associated with decreased tumor/NK cell conjugate formation with enzalutamide-resistant cells. Fulvestrant, a selective estrogen receptor degrader, restored the formation of target/NK cell conjugates and increased susceptibility to NK cell lysis in vitro. In vivo, fulvestrant demonstrated antitumor activity against enzalutamide-resistant cells, an effect that was associated with activation of NK cells. Conclusion NK cells are emerging as a promising therapeutic approach in prostate cancer. Modifying tumor plasticity via blockade of estrogen receptor with fulvestrant may offer an opportunity for immune intervention via NK cell-based approaches in enzalutamide-resistant CRPC.